tbuckley/cabot-search huggingface dataset:
TMIC-58. ALTERATIONS IN GLIOBLASTOMA TUMOR MICROENVIRONMENT TRANSCRIPTOME AFTER TREATMENT WITH PEMBROLIZUMAB
Authors: Nazanin Majd, Liu Yang, Garret Williford, Kristin Alfaro-Munoz, Pushan Dasgupta, Amy Heimberger, Kasthuri Kannan, Jason Huse, Krishna Bhat, John de Groot
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Immune checkpoint inhibitors (CPI) have failed to show survival benefit in glioblastoma. Understanding the alterations in the tumor microenvironment after treatment with CPI is crucial for development of immunotherapy in glioblastoma. We previously reported our window-of-opportunity trial of pembrolizumab in GBM (NCT02337686). In the current study, we obtained 8 paired glioblastoma tumors pre- and post-treatment with pembrolizumab and conducted RNA sequencing analysis to understand the alterations in the tumor microenvironment transcriptome in response to pembrolizumab. Method: We conducted bulk RNA-sequencing profiling and differential gene expression analysis to compare the expression levels of patient-derived glioblastoma pre- and post-treatment with pembrolizumab, while controlling for paired information. We performed gene enrichment analysis on the differentially expressed genes. We employed the single sample mww-GST method to assess the enrichment of various immune cell types that were previously identified, across the two groups. RESULTS Our analysis revealed 294 down-regulated and 259 up-regulated genes in the post treatment samples. The gene enrichment analysis demonstrated that the up-regulated genes were enriched in pathways related to the immune system. The single sample mwwGST analysis indicated a consistent overall up-regulation of expression in immune cell infiltration. Notably, T cell-related signatures, such as CD4, CD8, and NKT exhibited significantly higher infiltration in the post-treatment group. Interestingly, gene ontology analyses showed upregulation of phagocytosis and antigen presentation gene modules in the post-treatment samples. Additionally, we found neuronal components and genes related to hyperexcitability and synaptic connectivity with an overrepresentation of AMPA and DLG4 pathways in post-treatment tissues. CONCLUSION Our data show that in addition to the anticipated infiltration of myeloid and lymphoid cell populations, checkpoint blockade can also unexpectedly influence glioma-neuron interactions, which may represent additional immunotherapy targets in GBM. Further proteomic validation of infiltration of different cell types and their interactome in pre- and post-CPI treated tissue is warranted.
CNSC-05. LOCAL AND GLOBAL FUNCTIONAL CONNECTOME DISRUPTION IN PATIENTS WITH GLIOMAS
Authors: Giulia Sprugnoli, Laura Rigolo, Siddharta Pandit, Parikshit Juvekar, Meghan Faria, Yanmei Tie, Nicola Sverzellati, Simone Rossi, Alexandra Golby, Emiliano Santarnecchi
Journal: Neuro-Oncology (2023)

Abstract The aim of the study was to map the disruption of functional connectome in patients with gliomas using resting-state functional MRI (rs-fMRI) acquired before surgery (3T scanner). 54 patients with gliomas were included (M = 34, mean age = 50.8 y). Manual segmentation of lesions was performed on T1w and T2w MRI scans. Whole-brain measures of network centrality, modularity, integration and segregation were computed for a set of Regions of Interest (ROIs) including the Harvard Oxford anatomical atlas and tumor-related ROIs (i.e., edema, solid tumor, necrotic core). The analysis was performed on adjacency matrices obtained with a cost of 0.15, i.e. considering the 15% of the edges with the largest correlation coefficient values for each subject. A p&amp;lt; 0.05, two-sided, FDR corrected threshold was used for statistical analysis. In newly diagnosed patients (n = 18), we found a decrease of Integration (Degree, Global Efficiency) and Centrality (Betweenness Centrality) and an increase of Segregation (Local Efficiency) in the tumor ROIs compared to healthy brain regions. A similar integration/segregation imbalance pattern was present across the edema, solid tumor and necrotic core, with the edema being the most similar to healthy grey matter and the necrosis being the more altered, possibly reflecting tumor cells’ density and neuronal disruption. In patients at recurrence (n = 36), the same pattern was found, though with a less clear separation among tissue classes, possibly due to the altered anatomical/functional environment caused by functional plastic rearrangement and the effects the treatment(s). Finally, a significant correlation with overall survival was found for local efficiency values of the edema (p&amp;lt; 0.05, r 0,53=, R2 = 28%). We found significant alterations of functional connectome measures in brain regions affected by the tumor, with a decrease of network integration and an increase of network segregation measures characterizing different levels of tumor infiltration and potentially correlating with clinical outcomes.
EPID-04. EVOLVING SURVIVAL IN PATIENTS WITH LEPTOMENINGEAL METASTASES FROM SOLID TUMORS
Authors: Kiana Chabot, Isaiah Osei-Gyening, Rachel Estrera, Jonathan Yang, Elena Pentsova, Adrienne Boire, Jessica Wilcox
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The prognosis for patients with leptomeningeal metastases (LM) has been historically bleak, with an average survival &amp;lt; 4 months and limited treatment options. As modern therapeutics prolong the lives of cancer patients, the life expectancy of those with LM may also improve. This study aims to demonstrate survival trends in patients with LM over a 20-year time span. METHODS This is a single-institution retrospective analysis of patients diagnosed with solid tumor LM, excluding primary brain tumors, between 2002-2022. LM diagnosis was determined via unequivocal radiographic enhancement, CSF cytology, and CSF circulating tumor cell enumeration (CSF-CTC, cells/3mL). Patient characteristics, CSF-CTC enumeration at diagnosis, and therapeutic interventions post-LM were collected. Median overall survival (OS) with IQRs were calculated. RESULTS A total of 626 patients with LM were identified. The median age at LM diagnosis was 59 years (range, 13-86) with a female predominance (72.5%). Primary malignancy consisted of lung (45.2%), breast (35.7%), melanoma (4.0%), and other (15.1%). The 20-year median OS in patients with lung cancer was 4.8 months (1.9-13.0), breast cancer was 6.1 months (2.0-13.7), and melanoma was 7.1 months (2.8-14.5). Median OS was prolonged in patients with a CSF-CTC count ≤ 50 versus &amp;gt; 50 (8.9 vs 3.4 months, p&amp;lt; 0.0001). Patients who received LM-directed proton craniospinal irradiation (17.1%), photon involved-field radiation (45.5%), and no radiation (37.4%) had a median OS of 8.7 months (4.3-20.2), 4.3 months (1.5-9.1), and 3.4 months (1.2-12.5), respectively. Patients diagnosed with LM between 2017-2022 trended towards superior median OS (6.2 months, 2.2-14.0) compared to those diagnosed between 2002-2016 (5.3 months, 2.2-12.2). CONCLUSION In this largest known series of patients with LM, outcomes show signs of improvement. Superior survival trends emerge based on primary malignancy, early detection, and modern treatment modalities. Further analyses will define survival trends by patient characteristics, cancer subtypes, and systemic therapies.
DNAR-12. ATR INHIBITION AS A NOVEL RADIOSENSITIZATION STRATEGY FOR GLIOBLASTOMA
Authors: Suman Kanji, Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Pegah Ghamasaee, John Floyd, Bipasha Mukherjee, Sandeep Burma
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas (GBM) are lethal brain tumors for which surgical resection followed by ionizing radiation (IR) with concurrent and adjuvant Temozolomide (TMZ) remains the mainstay of therapy. GBMs are extremely radioresistant, and radiosensitization approaches are desperately needed for these tumors. IR induces DNA double-strand breaks (DSBs), and these lesions can be repaired either by error-prone non-homologous end joining (NHEJ) or the error-free homologous recombination (HR) pathway. Research in our and other laboratories has shown that the ATR kinase promotes the HR pathway. We therefore hypothesized that ATR inhibition would block DSB repair in rapidly-dividing GBM cells that are HR dependent but not in non-dividing normal brain cells that are dependent upon NHEJ for repair. We treated a panel of GBM cell lines and normal human astrocytes with the ATR inhibitor VX-803 and/or IR and assessed for multiple endpoints including HR, DSB repair, and cell survival. We found that VX-803 blocks HR and DSB repair in GBM cells but does not significantly affect repair in non-dividing normal human astrocytes. Hence, treatment with VX-803 sensitizes GBM lines to IR in vitro as measured by the colony formation assay. Next, PDX mouse models of GBM were treated with VX-803 followed by XRT, and monitored for tumor growth and survival. We found that the drug can cross the blood-brain barrier and, in conjunction with IR, block DNA repair in intracranial tumors, attenuate tumor growth, and consequently extend survival of tumor-bearing mice. Importantly, the drug does not significantly affect DSB repair in normal brain cells indicating that ATR inhibition might selectively block repair in GBM cells, thereby minimizing normal tissue toxicity. Our results indicate that regulation of HR by ATR is critical for optimal DSB repair, especially in rapidly-dividing GBM cells, and that ATR inhibition could be used to improve GBM radiotherapy in the clinic.
NIMG-07. LONG-TERM FOLLOW-UP OF SCHWANNOMA GROWTH BEHAVIOR IN ADULT SCHWANNOMATOSIS PATIENTS USING WHOLE-BODY MRI
Authors: Ina Ly, Vanessa Merker, Weni Cai, Miriam Bredella, Raquel Thalheimer, Jennifer Da, Hamilton Herr, Danielle Silverman, Christina Orr, Connie Chang, Gordon Harris, Scott R Plotkin, Justin T Jordan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The schwannomatoses include NF2-related schwannomatosis (NF2-SWN, formerly known as “NF2”) and non-NF2-related schwannomatosis (e.g. SMARCB1- and LZTR1-related schwannomatosis) and are caused by distinct germline pathogenic variants on chromosome 22. Patients may develop cranial, peripheral, and/or spinal nerve schwannomas. Except for vestibular schwannomas, the long-term growth behavior of schwannomas is unknown but this is important to guide patient surveillance and selection for treatment. Whole-body MRI (WBMRI) can detect whole-body schwannoma burden. METHODS 16 NF2-SWN and 12 non-NF2-SWN patients with WBMRI acquired between 2007-2010 underwent a repeat WBMRI between 2018-2022. Non-vestibular schwannomas were segmented on short tau inversion recovery (STIR) sequences. Tumor volume was calculated using a 3D tumor quantification software (3DQI). Tumor growth and shrinkage were defined as a volume change ³20% over the entire study period. RESULTS Median time between scans was 10.3 years. Median age was 43.5 years at baseline and 54 years at follow-up. Excluding resected tumors, 102 schwannomas (49 NF2-SWN, 53 non-NF2-SWN) were analyzed. 62/102 (61%) tumors grew &amp;gt;20% (65% NF2-SWN, 57% non-NF2-SWN); median growth was 96% in NF2-SWN and 94% in non-NF2-SWN. 24/102 (24%) tumors shrank &amp;gt;20% (20% NF2-SWN, 26% non-NF2-SWN); median shrinkage was 49% in NF2-SWN and 40% in non-NF2-SWN. 29 new tumors developed between scans (16 NF2-SWN, 13 non-NF2-SWN). Of 32 NF2-SWN tumors exposed to systemic or radiation therapy, 63% grew and 31% shrank. Of 7 non-NF2-SWN tumors exposed to treatment, 29% grew and 42% shrank. 11 non-NF2-SWN tumors shrank spontaneously without treatment. Spontaneous tumor shrinkage was not observed in NF2-SWN. CONCLUSIONS About 60% of SWN-associated schwannomas grow significantly over a decade. Spontaneous shrinkage is only observed in non-NF2-SWN tumors whereas, in NF2-SWN patients, about 60% of tumors grow despite treatment, suggesting a more aggressive tumor phenotype in NF2-SWN. Correlation of MRI findings with patient-reported outcomes and hormone exposure history are ongoing.
NCMP-25. TUMOR-RELATED EPILEPSY IN PATIENTS WITH BRAIN TUMORS (PBT): AN ACADEMIC INSTITUTION EXPERIENCE
Authors: Nynoshka Bassatt Cabrera, Ruham Alshiekh Nasany, Kehan Zhao, Sherif Elwan, Rebecca Rusnak, Roozbeh Tarighati Rasekhi, Shahram Izadyar
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain tumors are the second most common cause of intractable focal epilepsy. Seizures can be the presenting symptom of PBT or develop later in the disease course, impacting morbidity and quality of life. Despite the high prevalence of PBT-related epilepsy, there is a scarcity of literature to help better identify its unique features and characterizations that can guide medical management and reach a standardized approach for it. We present a retrospective review of a cohort of PBT-related epilepsy cases at a single academic institution. METHODS Records of patients with PBT seen at Upstate Medical University between 2012 and 2022 were reviewed. Inclusion criteria were: 18 years of age and older at the time of diagnosis and having at least one seizure that thought to be related to a PBT. Patients with history of previous epilepsy or psychogenic non-epileptic seizures were excluded. RESULTS Of the 1103 reviewed records, 293 patients (26.56%) met the inclusion criteria. Mean age at tumor diagnosis was 57.7 years +/- 16.6, and mean follow-up after tumor diagnosis was 17.9 months. Seizures were the initial presentation of the brain tumor in 166 (56.66%) patients. The most common tumor was grade 4 glioma in 45% of patients. Anti-seizure medications were started in 92.1%, and the most commonly used medication was levetiracetam in 75%. Number of patients who underwent total resection of the tumor was 123 (42.4%). On the last follow-up visit, 56% of patients remained seizure-free. CONCLUSION Patients with PBT often develop epilepsy that, at times, can be intractable. More than half of our patients experienced a seizure as the presenting symptom. Even though more than 90% were started on anti-seizure medications, only 56% remained seizure-free on follow-ups. Since seizures dramatically affect the quality of life, managing seizures in this patient population warrants further studies.
RADT-24. A PROSPECTIVE TRIAL EVALUATING THE EFFICACY OF REIRRADIATION TO BONY METASTASES WITH STEREOTACTIC BODY RADIATION THERAPY
Authors: Lubna Hammoudeh, Lauren Gunasti, Kee-Young Shin, Monica Krishnan, Lauren Hertan, Tracy Balboni
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Bone metastasis is common in advanced-stage cancer patients. While reirradiation of metastatic tumors offers significant symptom control, major limits exist on the possible dose delivered to previously irradiated disease sites. Stereotactic body radiation therapy (SBRT) offers the potential to avoid delivering toxic radiation doses to the spinal cord and other organs at risk by delivering large doses with steep dose gradients. METHODS We developed a prospective study including 44 patients with recurrent bone metastasis that were treated to assess the effectiveness of SBRT on local control at or before 6 months as a primary endpoint and local progression-free survival (LPFS), Progression-free survival (PFS), and overall survival (OS) as a secondary objective. RESULTS Patients median age was 62.5 years (22.7% female and 77.3% male). The majority of patients received reirradiation to a spinal lesion (29/44, 65.9%) of various primary disease sites predominantly prostate (13/44, 29.5%), lung (8/44, 18.2%), and renal cell (5/44, 11.4%). The most common dose prescriptions were 30 Gy in 5 fractions (24/44, 54.5%). Of the participants, 41 (93.2%) experienced local control at or before 6 months, with 3.6 median months to local progression for those who progressed. 48% and 36.5% of the cohort maintained LPFS at 2 years, and 3 years respectively with a local progression-free rate of 89.5% at 2 and 3 years. OS was maintained in 50.9% and 38.8% of patients at 2 years and 3 years respectively. CONCLUSION SBRT offers an effective and less toxic approach for the reirradiation of recurrent metastatic tumors as it can prevent associated toxicities to the surrounding normal tissues and maintain a local progression-free rate in a large percentage of patients. We believe that more clinicians should offer SBRT as an effective option for recurrent metastatic bone tumors especially involving the spinal vertebrae.
QLTI-14. CAN VARIANT ALLELIC FREQUENCIES OF DRIVER MUTATIONS PREDICT FALSE NEGATIVE MGMT PYROSEQUENCING RESULTS IN ADULT-TYPE DIFFUSE GLIOMAS?
Authors: Matthew McCord, Pouya Jamshidi, Vineeth Thirunavu, Lucas Santana-Santos, Erica Vormittag-Nocito, Stephanie Parker, Joseph Baczkowski, Lawrence Jennings, Jordain Walshon, Katy McCortney, Kirstyn Galbraith, Hui Zhang, Rimas Lukas, Roger Stupp, Karan Dixit, Priya Kumthekar, Amy Heimberger, Matija Snuderl, Craig Horbinski
Journal: Neuro-Oncology (2023)

Abstract MGMT promoter methylation predicts favorable temozolomide (TMZ) response in gliomas. Accurate test results depend on adequate tumor cellularity in analyzed samples, which is usually estimated (with sub-optimal accuracy) via light microscopy. We evaluated driver mutation variant allelic frequency (VAF) as a quantitative metric for tumor cellularity in MGMT promoter methylation testing. In a cohort of 691 adult-type diffuse gliomas, MGMT promoter methylation was tested by either pyrosequencing (N = 445) or DNA methylation array (N = 246). VAF of TERT and IDH driver mutations was quantified by next generation sequencing (NGS). We compared frequency of methylated (positive) and unmethylated (negative) results (Fisher’s exact test) and promoter methylation levels (unpaired t-test) according to VAF. We correlated MGMT promoter methylation, VAF, visually estimated tumor cellularity, and cellularity inferred from VAF via linear regression. We assessed survival (Log-Rank test) for 201 patients with IDH-wildtype GBM treated with TMZ. In samples with VAF &amp;lt;0.325 (identified by CutoffFinder), pyrosequencing yielded fewer positive results (37% versus 56%, p &amp;lt; 0.0001) and lower methylation levels (13% versus 19%, p &amp;lt; 0.0001) than samples with VAF≥0.325. Methylation array showed less frequent positive results at low VAF for IDH-mutant astrocytoma, but not for IDH-wildtype GBM. Microscopic examination tended to overestimate tumor cellularity, especially when VAF was low (R2 = 0.558). GBMs with unmethylated MGMT by pyrosequencing and TERT VAF &amp;lt;0.145 showed better responses to TMZ versus cases with VAF≥0.145 (median survival = 16.8 versus 13.3 months). Twelve pyrosequencing samples were re-tested by DNA methylation array and droplet digital PCR (ddPCR). RESULTS: changed for 2/6 samples with TERT VAF≤0.1, and 0/6 samples with VAF &amp;gt;0.1. Driver mutation VAF is useful for quality assurance in MGMT promoter methylation testing. Tumor samples with low VAF are at greater risk of false-negative results by pyrosequencing, which can be corrected by DNA methylation array and ddPCR.
NIMG-61. RADIOLOGICAL, CLINICAL, AND MOLECULAR ANALYSES UNRAVEL DISTINCT SUBTYPES OF ADULT GRADE 4 BUTTERFLY GLIOMAS AFFECTING THE PROGNOSIS
Authors: Ichiyo Shibahara, Yoko Tanihata, Kazuko Fujitani, Hajime Handa, Toshihiro Kumabe
Journal: Neuro-Oncology (2023)

Abstract Gliomas located at the corpus callosum (CC) and invading the bilateral hemispheres is known as butterfly gliomas (bG). Images of bG are frequently used as the hallmark of glioblastoma (GB); however, the molecular background and origins of bG remain unknown. We collected 37 bG patients, including 32 cases of GB and 5 cases of astrocytoma, WHO grade 4, IDH-mutant. Our dataset included extremely rare sequential radiological imaging before receiving a definitive diagnosis of bG. One case emerged from CC and subsequently became bG, whereas five cases emerged from the cerebral hemisphere and became bG, suggesting distinct radiological origins exist in bG. Reflecting this observation to further analysis, we subdivided the cohort into CC-type (n = 15) and hemispheric-type (n = 22) based on the ratio calculated by the tumor volume at CC and hemisphere. Survival analysis presented that CC-type was significantly poorer overall survival (OS) than hemispheric-type (P = 0.010), indicating that bG has clinically distinct two subtypes. Molecular analyses revealed that TERT promoter mutations and IDH1 mutations were observed in 73.3% and 0% in the CC-type, whereas 36.4% and 22.7% in the hemispheric-type, respectively. Other alterations such as MGMT promoter methylation, EGFR amplification/gain, CDKN2A hemi/homozygous deletion, and PTEN hemi/homozygous deletion remained the same between two groups. None of the patients had H3F3A, HIST1H3B, or BRAF mutations. In the hemispheric-type, the multisampling of hemispheric and CC specimens revealed accumulating alterations in the CC lesions, indicating an invasive trajectory from the hemisphere to the CC region. For the validation, we reviewed 993 MRI obtained from the public datasets (TCGA-GBM, CPTAC-GBM, IvyGap, and UPenn-GBM) and found the same trend: CC-type presented poor OS. bG is not a sole subtype with just extensive invasion from the hemisphere. Our results highlight the pathophysiology of bG and may influence its management.
NCMP-12. PREVALENCE OF RADIONECROSIS IN RECURRENT GLIOBLASTOMA
Authors: Nicolas Morin, Sylvine Carrondo Cottin, Stephan Saikali, Karine Michaud, Myreille D’Astous
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma (GBM) standard treatment consists of maximum and safe surgical resection, followed by radiation therapy in combination with temozolomide. Some patients show radiological and/or clinical deterioration soon after radiotherapy treatment. Early MRI changes, in the first 3 months following radiation is considered pseudo-progression. After this initial period, changes are considered as tumor recurrence. However, cases of early radiological deterioration have been related to radionecrosis. When tumor progression is suspected on imaging, it may causes treatment withdrawal or change. Therefore, for a certain percentage of patients, effective treatment could be abandoned in the presence of radionecrosis. METHODS The aim of the study is to assess the prevalence of radionecrosis at the Hôpital de l'Enfant-Jésus. This is a retrospective, observational case-control study evaluating recurrent GBM patients who underwent a second resection surgery. RESULTS The charts of 110 GBM patients with second resection were retrospectively reviewed (men: 62%, mean age: 58.3 years). Among these patients, we observed 87 cases of GBM recurrence as compared to 23 cases of radionecrosis (21%). No statistically significant difference was observed between the two groups regarding demographics, survival, Karnofsky performance status, type of surgery and treatments received. However, in the radionecrosis group, decreases in time between the 2 surgeries (55.3 vs. 24.3 weeks, p = 0.006) and in the number of cycles of chemotherapy received (5.7 vs. 3.7 weeks, p = 0.004) were observed as compared to GBM group. CONCLUSIONS This study characterizes demographically the patients with second surgery for suspicion of GBM in order to better adapt the treatments. Clinical and radiological data could not differentiate radionecrosis from true tumor recurrence or progression. A prospective study will be carried out as a second step, in order to determine radiological or molecular factors that could predict the presence of radionecrosis.